Most chemotherapeutic drugs act on both normal as well as cancerous tissues. As such, one of the challenges in treating cancerous tumors with chemotherapy is maximizing the killing of cancer cells while minimizing the harming of healthy tissue. Depending on the administration route (e.g., intravenous) and nature of the drug (e.g., its physical and pharmacokinetic properties), oftentimes only a small fraction of the dose reaches the target cells; the remaining amount of drug acts on other tissues or is rapidly eliminated. Thus, the efficacy of traditional cytotoxic chemotherapy drugs is limited by their adverse effects on non-cancerous tissue. Only a small fraction of the administered dose of drug reaches the tumor site, while the rest of the drug is distributed throughout the body. This causes undesirable damage to normal tissue when used in doses required to eradicate cancer cells, resulting in a limited therapeutic index. Use of the topoisomerase II poison doxorubicin (Dox) is limited by the induction of myelosuppression and cardiotoxicity. Site-specific drug delivery vehicles would make chemotherapy more effective and less toxic by increasing the amount of drug reaching the intended target.
A commonly used approach to address the issue of drug delivery to solid tumors is to attach the drug to a macromolecular carrier. Soluble polymeric carriers are attractive for systemic drug delivery because polymer-drug conjugates preferentially accumulate in tumors due to their enhanced microvascular permeability and retention and exhibit significantly lower systemic toxicity compared to free drug. Studies have shown that water soluble polymer carriers can overcome multidrug resistance. The most compelling evidence for the advantages of using polymer-drug conjugates over free chemotherapeutic agents for the treatment of cancer comes from extensive preclinical and clinical studies by Kopecek and colleagues on the use of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers as drug carriers.
Elastin-like polypeptide (ELP) is a protein comprised of a five amino acid repeat (XGVPG, where X is any amino acid except proline (SEQ ID NO: 1)). ELPs are attractive as polymeric carriers for drug delivery because they undergo an inverse temperature phase transition. Below a characteristic transition temperature (Tt), ELPs are structurally disordered and highly solvated. But, when the temperature is raised above their Tt, they undergo a sharp (2-3° C. range) phase transition, leading to desolvation and aggregation of the biopolymer. This process is fully reversible when the temperature is lowered below Tt.
The phase transition of these polypeptides may be exploited for use in drug delivery by applying focused, mild hyperthermia to the tumor site. Systemically injected ELP will remain soluble and freely circulate at normal body temperature. However, at localized sites where hyperthermia is applied to raise the tissue above the ELP's Tt, the polypeptide will aggregate and accumulate. Attachment of drugs to ELP offers the capability to specifically deliver these drugs to the desired tissue by focused application of externally applied hyperthermia. The use of hyperthermia has an added advantage of increasing vessel permeability. The ELP-based drug delivery system described here combines the advantages of macromolecular delivery, hyperthermia, and thermal targeting.
A previous study demonstrated the ability of ELP to deliver doxorubicin into the cell cytoplasm and induce cytotoxicity, but with no significant enhancement in cell toxicity in response to heat. Since the ultimate goal of drug delivery by ELP is to thermally target the chemotherapeutic, it is imperative that cytotoxicity be enhanced in response to temperature increase. The present inventors have discovered a thermally responsive drug carrier, generated by modifying the sequence of ELP to include additional targeting features, and the result was a drug delivery vector that achieved a 20 fold enhancement of cell killing in response to hyperthermia.